This proposal extends our previous transplantation studies with blastula- derived embryonic stem (ES) cells by comparing the morphological development and functional effects of this potentially optimal source of donor cells for transplantation with that of fetal ventral mesencephalic (VM) cells. The propagation of ES cells in culture can produce an almost unlimited supply of untransformed, totipotent cells that can be used for neural transplantation. We have previously shown that implementation of blastula-derived ES cells into the brain results in heterogeneous grafts containing cells of neuronal morphology and expressing neuronal markers characteristic of dopaminergic (DA) neurons (e.g. tyrosine hydroxylase positive and dopamine-beta hydroxylase negative). In addition, when placed into the DA-denervated striatum in a PD rat model, these cells selectively extended axonal processes into appropriate regions of the host brain. These studies utilized large bolus transplants (200,000 cells) and in some cases produced undifferentiated and non-neuronal cells. The proposed studies will systematically explore the effects of graft size (injected cell number and concentration) and of graft sites on the development of ES cells into DA neuronal phenotypes, and to determine their functional effects in two animal models of PD. By comparing the efficacy of ES cell grafts versus fetal VM cell grafts to ameliorate behavioral symptoms of DA cell loss, in both rodent and primate hosts, we can assess the potential of ES cells to serve as a cell source for transplantation therapies in Parkinson's disease.